The initial events leading to the development of autoimmune endocrine disease remain largely unknown and there have been some suggestions of a primary defect in the target cells. It is believed that normal human endocrine cells do not exprss HLA-DR antigens, which are largely restricted to immunocompetent cells. Therefore, the recent finding that a proportion of thyroid cells from glands affected by autoimmune disease displays HLA-DR determinants, as detected mouse monoclonal antibodies, has led to the hypothesis that aberrant HLA-DR expression might enable these cells to behave as "antigen-presenting cells" and thus trigger autoimmunity against themselves. The aim of this study is to elucidate the role that aberrant expression of HLA-DR antigenic determinants on human endocrine cells may have (A) in the initiation of the autoimmune process, and (B) in the enhancement and amplification of those pathogenic immune mechanisms leading to significant damage of the target gland and overt disease. The proposed experimental design specifically attempts to: (1) Determine whether the aberrant HLA-DR expression by follicular cells in thyroid autoimmune disease actually reflects the presence of an immunologically functional molecule bearing the relevant constituents (i.e. "self" allotypic determinants) to provide an appropriate "second signal" for autologous T cell recognition and activation. (2) Assess the possibility that this aberrant expression of HLA-DR determinants is not the initial cause of the autoimmune response, but rather the consequence of the infiltration by activated lymphocytes, possibly involving local release of lymphokines or cell-surface reactive autoantibodies. (3) Identify specific environmental (e.g. viral and hormonal) stimuli which might induce and modulate aberrant HLA-DR expression by thyroid cells in susceptible individuals. (4) Correlate the frequency of aberrant expression with particular HLA-DR haplotypes, to identify those which might be more "inducible" for their expression on endocrine cells. (5) Identify the prevalent lymphoid subpopulations of the intrathyroidal infiltrate which interact with autologous follicular cells in mixed cultures, to detect those lymphoid subsets which are actively "selected" to respond to (or induce) the aberrant HLA-DR expression. (6) Assess whether expression of HLA-DR antigens by human endocrine cells in thyroid and other (i.e. adrenal, pancreas, parathyroid and pituitary) glands constitutes a specific marker for autoimmunity, or whether that expression may also be detected on endocrine tissues which are either normal or affected by disorders unrelated to autoimmune reactivity.